ORIGINAL ARTICLE Print ISSN 1738-3684 / On-line ISSN 1976-3026

http://dx.doi.org/10.4306/pi.2016.13.4.413 OPEN ACCESS

Association between Medication Adherence and Duration

of Outpatient Treatment in Patients with Schizophrenia
Seiichiro Tarutani1,2 , Hiroki Kikuyama1,2, Munehiro Ohta1, Tetsufumi Kanazawa1,2,
Takehiko Okamura1, and Hiroshi Yoneda1,2
Department of Psychiatry, Shin-Abuyama Hospital, Osaka Institute of Clinical Psychiatry, Osaka, Japan
1

Department of Neuropsychiatry, Osaka Medical College, Osaka, Japan

2

ObjectiveaaMedication adherence is important in the treatment of schizophrenia, and critical periods during treatment may be associat-
ed with relapse. However, the relationship between adherence and duration of outpatient treatment (DOT) remains unclear. The authors
aimed to clarify the relationship between adherence and DOT at a psychiatric hospital in Japan.
MethodsaaFor outpatients with schizophrenia who regularly visit Shin-Abuyama hospital, the authors conducted a single questionnaire
survey (five questions covering gender, age, DOT, medication shortages, and residual medication) over one month period. Participants
were divided into two groups whether DOT were from more than one year to within five years or not. Mantel-Haenszel analysis and lo-
gistic regression analysis were performed on the data regarding the medication adherence.
ResultsaaEffective answers were received for 328 patients. The residual medication rate was significantly higher among those receiving
outpatient treatment from more than one year to within five years than five years than those receiving outpatient treatment for more
than five years or less than one year (p=0.016).
ConclusionaaThis survey suggests that there are critical periods during which patients are most prone to poor adherence. Because poor
adherence increases the risk of relapse, specific measures must be taken to improve adherence during these periods.
Psychiatry Investig 2016;13(4):413-419

Key WordsaaSchizophrenia, Medication adherence, Outpatients, Questionnaires, Critical period.

INTRODUCTION medication adherence,1-3 which itself has many influences.4,5

To date, numerous reports have considered different ways of
Schizophrenia is one of the most famous and serious diseas- checking medication adherence, including patient question-
es in psychiatric field. Despite of many efforts which human ing, relative questioning, medication adherence rating, elec-
try to understand the principle with many ways, we haven’t tronic monitoring using MEMS (Medication Event Monitor-
get all yet. Only we know that this disease is hard to cure and ing System),6-8 pill counting, and injection counting.9,10
needs continuous treatment. We psychiatrists know that one Several disparate factors are relevant to medication adher-
of the aims of treatment for patients with schizophrenia is pre- ence. Antipsychotics are clearly effective in the treatment of
vention of relapse or readmission. schizophrenia,11 second-generation antipsychotics appear to
Relapse in patients with schizophrenia is closely related to benefit from superior adherence rates12-16 and medication ad-
herence is also dependent on the type and formulation of the
Received: October 25, 2015 Revised: December 28, 2015 medicine used.17,18 Additionally, adherence may be poor be-
Accepted: December 31, 2015 Available online: March 23, 2016
 Correspondence: Seiichiro Tarutani, MD
cause many patients with schizophrenia often begin treatment
Department of Psychiatry, Shin-Abuyama Hospital, Osaka Institute of Clinical against their will,2,19 and may not have had the purpose of their
Psychiatry, 4-10-1, Nasahara, Takatsuki-shi, Osaka 569-1041, Japan
Tel: +81-72-693-1881, Fax: +81-72-693-3029, E-mail: [email protected]
treatment explained to them.20 Financial incentives, hope,
Department of Neuropsychiatry, Osaka Medical College, 2-7, Daigakumachi, and a recovery attitude are needed to maintain motivation
Takatsuki-shi, Osaka 569-8686, Japan
Tel: +81-72-683-1221, Fax: +81-72-683-4810, E-mail: [email protected]
during treatment.21,22 Particularly during involuntary treatment,
cc This is an Open Access article distributed under the terms of the Creative Commons the law of effect suggests that a favorable outcome would
Attribution Non-Commercial License (http://creativecommons.org/licenses/by- strengthen the action that produced it.23 Thus, collaborative
nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduc-
tion in any medium, provided the original work is properly cited. management in the sharing of therapeutic targets and under-

Copyright © 2016 Korean Neuropsychiatric Association 413

Adherence and Duration of Outpatient Treatment

standing patient motivation is key, raising the significance of pan.28 We set five questions covering gender, age, DOT at our
self-reporting. hospital, medication shortages, and residual medication.
As mentioned above, since the treatment of patients with Consecutive patients were recruited after they had seen their
schizophrenia often commences at involuntary admission, in- doctor, in order to reduce the effect of reporting bias. They
tensive outpatient care is needed to prevent a reduction in ad- were provided with a verbal explanation together with a writ-
herence.24 Tiihonen found that the mortality rate among pa- ten brief regarding the design of the study. Consent to partic-
tients with schizophrenia on antipsychotic medication was low ipate was then obtained verbally from the patients. The en-
in the 0–0.5 years period (HR 0.35). After that period, it wors- rolled participants were asked to complete the questionnaire
ened particularly in 0.5–2.0 years and was gradually better anonymously; the questionnaires were collected immediately
until 5.0 years. Further, it became lowest in 5.0–7.0 years (HR upon completion, and consent was assumed at that point.
0.73). In other words, risk of death became lower in bimodal The institutional review board of Shin-Abuyama Hospital,
both in 0–0.5 years and 5.0–7.0 years.25 Moreover, Robinson Osaka Institute of Clinical Psychiatry approved the use of this
reported that the risk of relapse was 16.2% within 1 year, survey. Questionnaires were kept securely and processed so
37.5% in 1–2 years, 9.4% in 2–3 years, 11.6% in 3–4 years and that patient identification was not possible.
7.2% in 4–5 years.26 It showed the same trend as Tiihonen’s
report; risk of relapse also became in bimodal. It became high- Questionnaire variables
er after one year of onset and lower the closer to five years. Responses to questions about gender and age were required
Therefore, they suggest that adherence is good within the for effective answers because age may be related to the DOT
first year of treatment, but worsens over the subsequent 1–5 and gender is a known prognostic factor in schizophrenia.
years. This is an important hypothesis, which to the best of We set a question with four choices: less than one year (<1
our knowledge has not yet been addressed in the literature. year); one year or more to fewer than five years (1–5 years);
The present cross-sectional study was therefore performed to five years or more to fewer than 10 years (5–10 years); and 10
clarify whether the reduced adherence observed at 1–5 years years or more (≥10 years). A multiple-choice question was
after the initiation of the treatment is helpful in the clinical set- chosen to stratify the answers and to encourage more accu-
ting. On the basis of these factors, we conducted a single ques- rate reporting by participants.
tionnaire survey to identify opinions of outpatients with schizo- The terms “medication shortage” and “residual medication”
phrenia at our hospital. are sometimes used to describe situations in which patients
were taking too many or too few medications, respectively.
METHODS However, since these situations can be affected by many fac-
tors in patients with schizophrenia, we defined them as “medi-
To clarify the relationship between medication adherence cation shortage”/“residual medication” from any cause, accord-
and the duration of outpatient treatment (DOT) at our hospi- ing to the self-reporting dichotomous response of “yes or no”
tal, we conducted a cross-sectional study using a single ques- on the questionnaire.
tionnaire survey among outpatients with schizophrenia who
regularly attended our hospital. Analysis of the critical period for adherence
The relationship between medication adherence and DOT To analyze the relationship between the DOT and medica-
was set as a primary endpoint. A secondary endpoint was iden- tion shortages or residuals, we formed two categorical data
tification of the factors influencing adherence, as analyzed us- groups based on the DOT: a “core period” group (1–5 years),
ing a regression model. and an “other” group (<1 year or ≥5 years). Our rationale was
that the critical period for medication adherence in patients
Subjects with schizophrenia occurs between one and five years from
Outpatients with schizophrenia at our hospital who attend- diagnosis.26 However, because of changes in where patients
ed regular outpatient appointments were invited to participate received treatment, the precise time of onset was not always
in this questionnaire-based survey. The study was conducted known and could have resulted in reporting bias. Therefore, we
for four weeks between January 10 and February 6, 2012, used the DOT at our hospital as a surrogate marker of duration
which is the shortest interval typically used by us for outpa- from onset to provide an objective indicator of adherence.
tient review. Schizophrenia was diagnosed based on code F20
of the International Classification of Diseases, Tenth Revision Statistical analysis
(ICD-10).27 The questionnaire was based on that of the Na- Frequencies and proportions were provided for all categori-
tional Federation of Mental Health and Welfare Party in Ja- cal data. The mean and standard deviation (SD) or the median

414 Psychiatry Investig 2016;13(4):413-419

 S Tarutani et al.

and range were provided for quantitative data. We applied the Table 1. Basic participant response (N=328)
Pearson χ2 test to determine the relationship between outpa- Characteristics N %
tient treatment duration and the rate of medication shortage Gender
or residual medication. Gender was analyzed as a stratification Male 167 51
factor by Mantel-Haenszel analysis, which provided odds ra- Female 161 49
tio (OR) for the categorical data, with 95% confidence inter-
Age (mean±SD)
vals (CI). When analyzing the outpatient treatment duration
Male 45.2±13.6 -
and the medication shortages or residuals, we considered all
Female 51.5±15.4 -
responses to be effective answers.
Duration of outpatient treatment
In the analysis using a logistic regression model to identify
at Shin-Abuyama Hospital
predictors affecting poor adherence, medication shortage or
residual medication were adopted as dependent variables, and <1 year 31 9
gender, age, and DOT as independent variables. The patients 1–5 years 92 28
were stratified into the following age groups: <30 years, 30–39 5–10 years 85 26
years, 40–49 years, 50–59 years, and ≥60 years. Since only three ≥10 years 116 35
of the patients were younger than 20 years, their data were No answer 4 5
pooled together with those from the <30-years age group. Medication shortages
p-values<0.05 were accepted as indicating significance, and “Yes” 24 7
all were two-tailed. All statistical analyses were performed us- “No” 297 91
ing IBM SPSS Statistics version 19 for Mac (Chicago, IL, USA).
No answer 7 2
Residual medications
RESULTS “Yes” 132 40
“No” 187 57
In total, 377 patients with schizophrenia visited our hospital
for treatment within the research period, of which 330 agreed No answer 9 3
to participate. However, effective answers were only received Medication shortages or residuals
for 328 patients, providing a response rate of 87%. Of these, “Yes” 140 43
65% (246/377) have continued to visit our hospital since onset. “No” 179 55
In addition, adding patients who visited our hospital more than No answer 9 3
five years (i.e., they had already experienced more than five The response rate was 87% (328/377) or outpatients that regularly
years from onset), 76% (286/377) of them met classification visited Shin-Abuyama Hospital. Effective answers were those ques-
criteria. tionnaires completed with data for sex and age
Table 1 summarizes the data for gender, age, DOT, and the and residual medication (316 effective answers). The core
medication shortages or residuals in the final sample. The period group comprised 91 patients, of which 47 had residu-
numbers of males and females were comparable but the age al drugs and 44 did not. The other group contained 225 pa-
of females tended to be significantly higher (Mann Whitney tients, of which 83 had residual drugs, and 142 did not. There
test, p<0.001). There were 321, 319 and 319 effective answers was a significant difference between the groups (χ2=5.829,
to the questions about outpatient treatment duration, medi- df=1, p=0.016) that remained after stratification by gender
cation shortages, and residual medication, respectively. As (OR 1.83, 95% CI 1.12–2.99, p=0.016) (Figure 1).
demonstrated, 7% (24/321) had medication shortages, 41% And Table 2 shows the results of the χ2 test between the
(132/319) had residual medication, and 44% (140/319) had DOT and the medication shortages and residuals (316 effec-
both medication shortages and residuals. tive answers). The core period group comprised 91 patients,
Table 2 shows the results of the χ2 test between the DOT at of which 48 patients had medication shortages or residuals,
our hospital and medication shortages (318 effective an- but 43 did not; the corresponding values for the other group
swers). The core period group (1–5 years) comprised 91 pa- were 225 (total), 90 (yes), and 135 (no). The ratio of medica-
tients, of which 84 had no drug shortages and seven did. The tion shortages and residuals was significantly higher in the
other group (<1 year or ≥5 years) was comprised of 227 pa- core period group (χ2=4.280, df=1, p=0.039). Significance re-
tients, of which 210 had no drug shortages and 17 did. There mained after stratification by gender (OR 1.67, 95% CI 1.02–
were no significant differences between the results (χ2=0.004, 2.73, p=0.040) (Figure 2).
df=1, p=0.951). And it shows the χ2 test between the DOT The results of the logistic regression analysis to identify pre-

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Adherence and Duration of Outpatient Treatment

Table 2. Comparing the duration of outpatient treatment and medication shortages or residual medications
Duration of outpatient treatment
χ2, df, p
1–5 years <1 year or ≥5 years Total
Medication shortages (N=318) 0.004, 1, 0.951
“Yes” 7 17 24
“No” 84 210 294
Total 91 227 318
Residual medications (N=316) 5.827, 1, 0.016
“Yes” 47 83 130
“No” 44 142 186
Total 91 225 316
Medication shortages or residuals (N=316) 1.28. 1, 0.039
“Yes” 48 90 138
“No” 43 135 178
Total 91 225 316

* Whole data * Whole data

(%) Male (%) Male
52 53 53 52 53
60 50 Female 60 Female
(47/91) (22/44) (25/47) (48/91) (23/44) (25/47)
50 50 40 39 41
37 38 36 (90/225) (45/116)(45/109)
40 (83/225) (44/116)(39/109) 40

30 30

20 20

10 10

0 0
1–5 years <1 year or ≥5 years 1–5 years <1 year or ≥5 years
‘core period’ group other group ‘core period’ group other group
The period of outpatient treatment at our hospital The period of outpatient treatment our hospital

Figure 1. The rate of residual medication. Pearson’s χ test to deter-

2
Figure 2. The rate of medication shortaages or residuals. Pearson’s
mine the association with the period of outpatient treatment to “our” χ2 test to determine the association with the period of outpatient
hospital and the ratio of the rest of prescribed drugs. And we ana- treatment to “our” hospital and the ratio of the rest of prescribed
lyzed gender as stratification factor in Mantel-Haenszel analysis. drugs. And we analyzed gender as stratification factor in Mantel-
OR 1.83, 95% CI 1.12–2.99. *p=0.016. Haenszel analysis. OR 1.67, 95% CI 1.02–2.73. *p=0.040.

dictors affecting poor adherence are presented in Table 3. Al- and “DOT at our hospital” were considered to be similar in
though none of the independent variables exhibited statisti- this survey. There was evidence of an association between out-
cal significance, there tended to be an increased risk of poor patients with schizophrenia visiting our hospital during the
adherence among those with a DOT of 1–5 years (OR 1.602, core period (1–5 years) and not taking medications, as indi-
95% CI=0.961–2.670, p=0.071). cated by the rate of residual medications during this time.
Approximately 40% of patients with schizophrenia are re-
DISCUSSION ported to have poor adherence,29 which is comparable to our
data. Additionally, studies have reported that medication ad-
We used a cross-sectional, questionnaire-based survey to herence and relapse are correlated, particularly during critical
determine if there was an association between the DOT at periods30 between one and five years after the onset of schizo-
our hospital and residual medication among outpatients with phrenia.26 Many studies have reported a relationship between
schizophrenia. In this survey, since 65% of all patients with relapse after clinical response to medication after the first ep-
schizophrenia who visited our hospital within research peri- isode of schizophrenia or schizoaffective disorder, but few
od visited from onset and 76% of them met classification cri- have considered the relationship between adherence and DOT
teria. Therefore, it might be suggested that “DOT from onset” at a single institute. This may be partially due to different med-

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 S Tarutani et al.

Table 3. Logistic regression analysis to identify predictors of poor medication adherence

B SE Wald Exp (B) 95% CI p
Gender
Male 1.00
Female 0.011 0.314 0.001 1.011 0.546–1.870 0.973
Age
–29 1.00
30–39 0.074 0.476 0.024 1.077 0.424–2.735 0.877
40–49 -0.449 0.477 0.887 0.638 0.250–1.626 0.346
50–59 -0.316 0.530 0.356 0.729 0.258–2.059 0.551
60– -0.479 0.498 0.926 0.619 0.233–1.644 0.336
DOT
<1 year or ≥5 years 1.00
1–5 years 0.471 0.261 3.264 1.602 0.961–2.670 0.071*
*p<0.1. DOT: duration of outpatient treatment, SE: standard error, CI: confidence interval

ical models operating throughout the world, such as the uni- ator and reporting biases remain important issues. In addi-
versalistic, social insurance, and market-oriented models. tion, it can be very difficult to identify the precise time of onset
Our results revealed a significantly high rate of residual of symptomatic relapse, which is an important social predic-
medication in the core period group, which corresponded to tor. Differences in evaluating the time of onset of subjective
the critical period previously reported, suggesting that poor and objective symptoms can be caused by differences in the
adherence in this period has some relationship with relapse therapeutic relationship, available support systems, cultural
of schizophrenia, regardless of gender. This stresses the impor- backgrounds and protective factors.36
tance of treatment early in the course of the disease. Moreover, It is important to offer appropriate biological pharmaco-
the critical period may be particularly important because it therapy. The choice of antipsychotic is recognized to be a cen-
often represents a period when the patient starts to accept life tral problem in non-adherence and subsequent relapse. We
with schizophrenia and moves from involuntary treatment to can no longer ignore the fact that second-generation antipsy-
self-actualization. While the regression analysis yielded no chotics have superior adherence, and that long-acting depot
statistical significance, the data show that there tended to be injections offer alternative definitive treatment.17,37 Equally, we
an increased risk of poor adherence with a DOT of 1–5 years. must remember that these do not solve the fundamental is-
A larger sample size would improve the statistical power of sues with non-adherence.
this data. The data support the hypothesis that medication Psychotherapy is also important for patients with schizo-
adherence among schizophrenic patients is reduced after a phrenia. Indeed, psychoeducation,38 social-skill training,39,40
DOT of 1–5 years. cognitive remediation therapy,41 and cognitive behavioral
Although at least 21 days are normally required for habitu- group therapy42,43 have all proven effective. The distribution
ation of behavior,31 more time may be needed to habituate fol- and efficacy of these structured programs in Japan is hard to
lowing a significant event or task. Habit is defined as a learned qualify. Despite the presence of 24980 clinical psychologists
behavioral response that has become associated with a par- in Japan in 2013,44 the Japanese government does not provide
ticular situation, especially one that is frequently repeated.32 a recognized national qualification and does not allow or fund
Assuming that clinical deterioration in schizophrenia is not acute-care psychotherapy. In contrast, there are about 18549
fixed, it may be that it takes 1–5 years for patients to habituate chartered psychologists in the UK in 2013 and 106500 prac-
to medication that was initiated on an involuntary basis. ticing psychologists in the US in 2012.45,46 Therefore, staff as-
Over 82% of patients with schizophrenia regularly visit hos- signment may be very different from that in the UK and the US.
pital at 4-week intervals for outpatient treatment,28 and many Social assistance is available for patients in Japan during spe-
with unstable conditions visit every 2–4 weeks. The response cific treatment periods. However, this does not specify con-
rate of 87% to this survey may reflect outpatients with unsta- tinual visitation to a specific mental health institution. Thus,
ble illness. It is essential that we objectively evaluate the DOT when treatment difficulties occur or patients become frustrat-
significantly related to adherence. Although the duration of ed, they can readily change where they receive treatment. Cou-
untreated psychosis is a useful predictor of outcome,33-35 evalu- pled with the fact that medical institutions do not share a

www.psychiatryinvestigation.org 417
Adherence and Duration of Outpatient Treatment

common reporting format, it can be difficult to share patient Medication adherence among outpatients with schizophre-
information concerning disease onset. nia may be related to the DOT at a mental health institution,
Hospitalization and follow-up are ongoing issues with re- especially in countries that employ a social insurance model
search into relapse rates. Many reports have stated that relapse of healthcare. To encourage patients with schizophrenia to
of schizophrenia requires hospitalization.47 However, when continue outpatient treatment over critical periods, it is vital
patients are free to decide on which institution to attend, there to employ evidence-based management. Our survey suggests
can be a loss in follow-up because it becomes impractical to that we need to take specific measures to ensure patients have
find the details of other admissions. In countries with a social reduced risks of non-adherence during critical periods.
insurance model, the medical system encourages freedom of
choice and personal responsibility. However, in October 2011, Acknowledgments
There are no funding sources for this study. And the authors declare no
private mental health institutions in Japan were chosen 18 conflict of interest. We thank the nursing staff in outpatient department
times more often than public mental health institutions.48 Fur- (Tamayo Danjo, Miki Kohri, Junko Umeno, Kinue Inoue, Yukie Shoji, Shi-
thermore, economic costs are sometimes more pressing than zuko Nakatani, Naoko Kadota, and Yuriko Matsui) of Shin-Abuyama hos-
pital for their efforts in collecting the questionnaires.
the provision of mental healthcare services in many non-spe-
cialist medical institutions that offer a greater range of services.
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